Intracellular second messenger cAMP is synthesized by adenylate cyclase, and hydrolysed to 5'-AMP by a family of phosphodiesterase(PDE) isozymes. Up to now, at least five isozymes of PDE have been identified, and their distributions have been studied in variety of tissues [Trends Pharm. Sci., 12, 19, (1991)]. Among five PDE subtypes, type IV PDE was found to be a dominant isozyme in inflammatory cells. Increase in intracellular concentration of CAMP by inhibition of cAMP degradation with PDE inhibitors has been shown to inhibit several kind of inflammatory cells. In addition, airway smooth muscle tone are regulated by cAMP, increase in intracellular concentration of cAMP result in relaxation of airway smooth muscles [Thorax, 46, 512, (1991)]. Thus, a compound which inhibit type IV PDE may exhibit beneficial effects on inflammatory disease such as asthma [J. Pharmacol. Exp. Ther., 266, 306 (1993)], dermatitis [Br. J. Pharmacol., 112, 332 (1994)], and autoimmune diseases including multiple sclerosis [Nature Medicine, 1, 244 (1994)], and rheumatoid arthritis [Clin. Exp. Immunol., 100, 126 (1995)]. Because distribution of PDE isozymes are not same in different organs, specific inhibitor of type IV PDE may also decrease some adverse effects observed in nonspecific PDE inhibitor such as theophylline. Rolipram having the following formula (JP-A-50-157360 publication) is known as a compound having a specific inhibitory action against type IV PDE. ##STR2##
Other compounds having a specific inhibitory action against type IV PDE are known (WO 94/10118, WO 94/12461, JP-A-5-117259, JP-A-7-101861, WO 95/03794, WO 95/08534, etc.). However they have not been clinically applied up to now, and therefore, development of more useful compounds is desired.
JP-A-60-89421 discloses a compound having the following formula (II): ##STR3##
wherein R.sub.1 represents an isopropyl group or t-butyl group; R.sub.2 represents a hydrogen atom, C.sub.1 to C.sub.4 alkyl group, C.sub.1 to C.sub.4 alkoxy group, hydroxy group, or amino group; and R.sub.3 represents a hydrogen atom or methyl group, as a .beta.-adrenergic receptor antagonist. JP-A-4-234369 discloses a compound having the following formula (III): ##STR4##
wherein Ar represents a phenyl group substituted with two groups, a pyridyl group, or thienyl group; and R.sub.3 represents a C.sub.1 to C.sub.5 alkyl group, --CH.sub.2 Ph group, or --CH.sub.2 CH.sub.2 Ph group, as a synthesis intermediate of a pharmaceutical composition. JP-A-50-37800 discloses a compound having the following formula (IV): ##STR5##
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 represent a hydrogen atom or lower alkyl group; and A represents a hydrogen atom or oxygen atom, as a synthesis intermediate of a compound exhibiting an analgesic action. WO 92/06963 discloses a compound having the following formula (V): ##STR6##
wherein R.sub.1 and R.sub.2 represent a methoxy group, difluoromethoxy group, ethoxy group, C.sub.4 to C.sub.7 cycloalkoxy group, or C.sub.3 to C.sub.7 cycloalkylmethoxy group, as a synthesis intermediate of a compound exhibiting a bronchospasm relieving action. However, the fact that the compound having the above formula (V) per se exhibits the bronchospasm relieving action is not described at all.